The apical chloride/base exchanger in kidney proximal tubule and gastrointestinal tract works in parallel with NHE3 and is essential for chloride absorption and fluid homeostasis. However, less is known about the molecular identity and the main functional mode of this exchanger. SLC26A6, also known as PAT1 or CFEX, is a member of a large, highly conserved family of ion transporters (designated as SLC26A) many of which mediate anion exchange. SLC26A6 can mediate CI'/HCO3-, Cl/formate and Cl-/oxalate exchanges, indicating that it is an ideal candidate for apical Cl/base exchange in proximal tubule. Our experiments demonstrate that SLC26A6 mediates CI-/HCO3- exchange, is located on the apical membrane of proximal tubule, small intestine and tubulovesicles of gastric parietal cells, and is upregulated by NH4+, a naturally occurring chemical in kidney proximal tubule and small intestine. We further demonstrate the presence of an apical CI/HCO3- exchange in rat and mouse isolated microperfused proximal tubules and in tubulovesicles of gastric parietal cells. We hypothesize that SLC26A6 is the main apical anion exchanger in kidney proximal tubule and duodenum, functions predominantly as a CI-/HCO3- exchanger under physiologic conditions and is responsible for the bulk of chloride absorption. In the stomach, PAT1 may be essential for neutralizing the luminal acidity of H-K-ATPase-containing vesicles during the resting state. The purpose of the current proposal is to ascertain the role of the apical CI-/IHCO3- exchanger and PAT1 (SLC26A6) in chloride (and fluid) absorption in kidney proximal tubule and gastrointestinal tract. Toward this end, we propose to: 1. Characterize the apical CI/HCO3- exchanger in isolated microperfused proximal tubule and ascertain its role in chloride reabsorption in the presence of solutions mimicking proximal tubule milieu, 2. Ascertain the role of SLC26A6 in apical Cltbase exchange and cr reabsorption in kidney proximal tubules using SLC26A6 (PAT1) null mice, 3. Examine the acute and chronic regulation of SLC26A6 (PAT1) and apical CI-/HCO3- exchanger in kidney proximal tubule, and 4. Determine the role of SLC26A6 in gastric and intestinal function, including CI absorption and protection against acid injury in the duodenum and acid secretion in the stomach, using SLC26A6 null mice. Insight into the functional and molecular properties of PAT1 and apical CI-/HCO3- exchange in kidney proximal tubule and upper gastrointestinal tract in physiologic states and examination of PAT1 deficient mice should significantly enhance our understanding regarding the apical CI-/base exchanger and cr absorption in epithelial tissues. They should further facilitate future investigations into the role of this transporter in pathophysiologic states affecting electrolyte and acid-base homeostasis.